The treatment of three particular disorders-pain, depression and Parkinson's disease-is notoriously vulnerable to placebo effects. A striking similarity between these disorders is their dependence on midbrain dopamine and endogenous opioid systems, two neurochemical systems considered fundamental to anticipatory states and addiction. Here, we posit that study of placebo effects offers invaluable insights into how pain, reward, and addiction processes intersect. This is particularly timely, as studies of placebo effects in humans have exploded over the past decade, laying a strong foundation on which to base mechanistic preclinical studies. However, there are virtually no preclinical models of placebo effects of which we are aware. Thus, in Aim 1 we will first establish and validate a preclinical behavioral model of placebo-induced analgesia, based on Pavlovian conditioning to morphine and responding in a novel operant orofacial pain assay. Importantly, this model is able to encompass the cognitive and affective aspects of placebo responses. Second, as stress produces behavioral depression in humans and animals, we will test the hypothesis that a pre-existing pain state attenuates placebo-induced analgesia, based on the rationale that pre-existing pain dampens activity in one of the same neural systems, i.e., dopamine. In Aim 2, we will seek neural correlates of placebo-induced behaviors by simultaneously evaluating dopamine levels in the nucleus accumbens and prefrontal cortex during establishment and expression of placebo- induced analgesia under non-pain and pre-existing pain states. We hypothesize that placebo responses are encoded in midbrain dopamine activity in a similar manner to behaviors typical of drug addiction (e.g., sensitization of mesolimbic dopamine release), and in doing so, we aim to uncover a direct link between the fields of pain, anticipatory behavior, reward, and addiction. Such an understanding is critical to developing novel treatments for pain that avoid addiction, as well developing appropriate strategies for treating pain in addicts and depressed individuals. By combining our specialties in the fields of pain, addiction, and placebo research, we are ideally positioned to develop and complete this line of investigation. PUBLIC HEALTH RELEVANCE: Through these studies, we aim to convincingly demonstrate that animals, like humans, show placebo and nocebo effects. In doing so, we will address the role that these effects have in determining the efficacy of drugs used in the treatment of pain, depression and addiction, in addition to uncovering the associated neurobiology.